Formation of excess scar tissue, called fibrosis in organs, affects billions of people world-wide. Fibrosis of the lung, heart, kidney, liver, eye, bone marrow, etc. is responsible for morbidity and mortality. Scarring is a consequence of the normal wound healing response. However, scar formation can be exuberant leading to hypertrophic scarring and/or fibrosis that can ultimately lead to a loss of tissue function (Friedlander M., “Fibrosis and diseases of the eye,” J. Clin. Invest. 117:576-586 (2007); Noble et al., “Pulmonary fibrosis: patterns and perpetrators,” J. Clin. Invest. 122:2756-2762 (2012); Bahn R. S., “Graves' ophthalmopathy,” N. Engl. J. Med. 362:726-738 (2010); and Hinz B., “Formation and function of the myofibroblast during tissue repair,” J. Invest. Dermatol. 127:526-537 (2007)). While there is a major knowledge gap as to why scarring sometimes proceeds out of control, hypertrophic scarring usually results from physical injury, such as laceration or surgery or from burns either thermally, chemically or radiation induced (Niessen et al., “On the nature of hypertrophic scars and keloids: a review,” Plast. Reconstr. Surg. 104:1435-1458 (1999)). For example, an unfortunate consequence of severe heat-induced burns is the development of debilitating hypertrophic scars (Gauglitz et al., “Hypertrophic scarring and keloids: pathomechanisms and current and emerging treatment strategies,” Mol. Med. 17:113-125 (2011)). Chronic inflammation and autoimmune disease can also lead to aberrant tissue reorganization and scarring (Lehmann et al., “Immune mechanisms in thyroid eye disease,” Thyroid: official journal of the American Thyroid Association 18:959-965 (2008); Phan S. H., “The myofibroblast in pulmonary fibrosis,” Chest 122:286S-289S (2002)). Thyroid eye disease (TED) is an example of an autoimmune disease in which immune cells target the muscle and connective tissue in the ocular orbit leading to orbital tissue remodeling and excessive scarring (Bahn R. S., “Graves' ophthalmopathy,” N. Engl. J. Med. 362:726-738 (2010); Kuriyan et al., “The eye and thyroid disease,” Curr. Opin. Ophthalmol. 19:499-506 (2008)). While aberrant scarring is observed in numerous pathologies, there are few, if any effective therapies that limit or prevent scarring.
The key effector cell in scar formation is the contractile and secretory myofibroblast (Hinz et al., “The myofibroblast: one function, multiple origins,” Am. J. Pathol. 170:1807-1816 (2007)). Myofibroblasts are derived from tissue resident fibroblasts, epithelial-mesenchymal transitions, circulating fibrocytes, mesenchymal stem cells or other progenitor cells (Desmouliere et al., “Tissue repair, contraction, and the myofibroblast,” Wound Repair Regen. 13:7-12 (2005)). Myofibroblasts highly express alpha-smooth muscle actin (αSMA), an important protein required for wound contraction, and these cells produce large amounts of extracellular matrix (ECM) material including collagen, fibronectin and glycosaminoglycans (Hinz et al., “Recent developments in myofibroblast biology: paradigms for connective tissue remodeling,” Am. J. Pathol. 180:1340-1355 (2012); Smith et al., “Fibroblasts as sentinel cells. Synthesis of chemokines and regulation of inflammation,” Am. J. Pathol. 151:317-322 (1997)). The contraction of myofibroblasts and their excessive production of ECM material such as collagen result in rigid tissue formation and increases in tissue size. In addition to their contractile phenotype, myofibroblasts also secrete a variety of cytokines including IL-6, MCP-1 and TGFβ that recruit immune cells and lead to further myofibroblast formation (Micallef et al., “The myofibroblast, multiple origins for major roles in normal and pathological tissue repair,” Fibrogenesis & Tissue Repair 5:S5 (2012)).
Despite the magnitude of the problem there are no effective anti-scarring approaches of consequence. New directed therapies to prevent scar formation are urgently needed. It would be desirable, therefore, to identify small molecule compounds that possess an ability to disrupt myofibroblast differentiation and thereby modulate scarring or fibrosis.
The present invention is directed to overcoming these and other deficiencies in the art.